The benefits of antiretroviral therapy (ART) to HIV-infected patients are significant. However, ART interruption is coupled with a rapid rebound in plasma viremia. This rebound signifies the enigma surrounding ART - its inability to completely eradicate HIV. There is a definite need for an in vivo model where these mechanisms can be elucidated and therapeutic interventions aimed at virus eradication can be evaluated. Novel humanized mice (bone marrow-liver-thymus or BLT mice) developed in our laboratory could serve effectively in this capacity. Humanized BLT mice exhibit systemic reconstitution (including in the gut and vaginal mucosa) with a complete and functional human immune system. The functionality and usefulness of BLT mice in the study of HIV persistence and eradication will become evident when the following aims are completed, wherein the parameters of viral persistence will be established and novel eradication approaches will be tested (Project 2). The long term goal of our project is to develop and implement an in vivo animal model in which novel protocols for HIV-1 eradication can be evaluated. This project will first implement a novel integrase inhibitor (provided by Project 1) and two reverse transcriptase inhibitors of proven efficacy in HIV-infected BLT mice, in the durable suppression of viremia to allow the detailed study of persistence and latency. After the establishment of this model, this project will evaluate the effect of novel reagents to disrupt latency that have been selected in Project 1 and validated in primary human cells in Project 3. Anti-latency therapy in hypothesized to alter the kinetics of rebound viremia after ART interruption, and the recovery of replication-competent HIV in cell populations harvested from durably suppressed animals. In addition, we will compare the effects of ART versus those of intensified therapy to further reduce the viral reservoir and augment the effect of anti-latency therapy. Specific Aim 1: To establish decay and viral rebound dynamics of HIV in BLT mice during ART and after its discontinuation. Specific Aim 2: To characterize the nature and the anatomical location of viral reservoirs that persist in BLT mice undergoing ART. Specific Aim 3: To characterize the effect of select interventions (anti-latency therapy) on viral burden in the latent reservoir(s)